Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection
Background
It is well known that CD4+CD25+ regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. Therefore, therapeutic agents that capable of enhancing the number and activity of this T-cell subset are highly desirable.
Methods
The present study was designed to investigate the effects of superagonistic CD28-specific monoclonal antibody (supCD28 MAb) on preferentially expanded rat naturally occurring CD4+CD25+ Treg (nTreg) cells and its applicability in cardiac transplantation.
Results
A single administration of supCD28 MAb preferentially proliferated nTreg cells. The increase of Foxp3 expression and polarization toward a Th2 cytokine profile correlated with decreased production of interferon-γ and increased production of interleukin-4 and -10 in the expanded CD4+CD25+ Treg subset, which was capable of suppressing CD4+CD25− T-cell proliferation after purification. Furthermore, supCD28 MAb administration revealed that nTreg cells were preferentially proliferating in vivo and recruited into the grafts, resulting in significant prolongation of full MHC-mismatch cardiac graft survival.
Conclusions
Our data demonstrate that supCD28 MAb targets expansion of nTreg cells in vivo and maintains and enhances their regulatory functions, which represents a major advance toward the therapeutic use of polyclonally activated Treg cells as cellular therapy for treatment of allograft rejection.
aLaboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
bAIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
cShizuoka Laboratory Animal Center, Ltd., Shizuoka, Japan
dDepartment of Urology, Osaka Medical College, Osaka, Japan
eDepartment of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan
fInstitute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
gDivision of Immunology, Research Institute for Biological Science, Science University of Tokyo, Chiba, Japan.
Reprint requests: Xiao-Kang Li, MD, Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Telephone: +81-3-3416-0181. Fax: +81-3417-2816.
Supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (14370367, 13671250 and 17390355).
ABSTRACT